DESCRIPTION OF RESEARCH INTERESTS:

Dr. Ogiso's ultimate research interest is mitochondrial energy metabolism in human health and disease. While the main role of mitochondria is to generate ATP, mitochondria perform many other critical functions including lipid/steroid synthesis, Ca2+ regulation, iron regulation, heme/iron-sulfur cluster synthesis, cell signaling cascades, and so on. Mitochondria are central to eukaryotic cell function and survival. Therefore, mitochondrial dysfunctions lead to a remarkably wide range of human diseases including heart failure, type 2 diabetes, and neuronal degenerative diseases. Dr. Ogiso’s current focus, complex I, is the entry enzyme of the mitochondrial respiratory chain. Complex I plays a central role in cellular aerobic energy metabolism. Presently, we are tackling one of the most challenging fundamental questions in bioenergetics: How is electron transfer is linked to vectorial H+ translocation in complex I? This question has remained unanswered even 30 years after Mitchell’s Nobel Prize for the chemiosmotic theory.

We are also interested in how to rescue complex I dysfunction. The most crucial and unique function of complex I is NADH oxidation. Impaired NADH oxidation in mitochondria leads to lactic acidosis, high NADH/NAD+ ratio, increased reactive oxygen species (ROS), and eventually, apoptosis. One effective strategy is a complementation of dysfunctional complex I with alternative NADH dehydrogenases which can fix altered NADH/NAD+ balance and protect cells from excessive ROS generation. We are now searching for another strategy to modulate NADH/NAD+ levels by investigating the NAD+ metabolism. NAD+ precursors have been shown to slow down aging and extend lifespan. Considering the pivotal role of NAD+ in the regulation of DNA repair, stress resistance, and cell death in addition to its role in cellular respiration and energy production, NAD+ synthesis through the kynurenine pathway and/or salvage pathway is an attractive target for therapeutic intervention in mitochondrial diseases.